Levodopoa and Carbidopa Intestinal Gel and Methods of Use

ABSTRACT

The present disclosure relates to (a) an improved pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent (b) methods of producing the pharmaceutical composition and (c) methods of treating Parkinson&#39;s disease and associated conditions comprising administering the pharmaceutical composition to a subject with Parkinson&#39;s disease.

PRIORITY STATEMENT

This U.S. patent application is a divisional application claimingpriority to U.S. patent application Ser. No. 15/001,392, filed Jan. 20,2016, which claims the benefit of U.S. Provisional application62/105,565 filed 20 Jan. 2015 and 62/272,922 filed 30 Dec. 2015. Theentire contents of each patent application recited herein are herebyincorporated by reference.

FIELD OF THE INVENTION

The present disclosure relates to (a) an improved pharmaceuticalcomposition comprising levodopa and carbidopa and (b) methods oftreating Parkinson's disease and associated conditions comprisingadministering the pharmaceutical composition to a subject withParkinson's disease.

BACKGROUND OF THE INVENTION

Parkinson's disease is a chronic and progressive neurodegenerativecondition characterized by reduced levels in the brain of theneurotransmitter dopamine (i.e., 3,4-dihydroxyphenethylamine).Administration of L-dopa currently is the most effective therapy fortreating a patient with Parkinson's disease. L-dopa, which unlikedopamine can cross the blood-brain barrier, is enzymatically convertedin the brain to dopamine resulting in an increase in dopamine levels:

The conversion of L-dopa to dopamine is catalyzed by aromatic L-aminoacid decarboxylase, a ubiquitous enzyme that promotes central as well asperipheral metabolism of L-dopa to dopamine. A relatively large dose ofL-dopa is required to achieve therapeutically effective dopamine levelsin the brain. Administration of such large L-dopa doses results inelevated peripheral dopamine levels that can cause nausea in somepatients. To overcome these problems, L-dopa generally isco-administered with a peripheral aromatic L-amino acid decarboxylaseinhibitor such as carbidopa (i.e.,(2S)-3-(3,4-dihydroxy-phenyl)-2-hydrazino-2-methylpropanoic acid):

Co-administration of carbidopa with L-dopa inhibits the peripheralmetabolism of L-dopa to dopamine, which significantly reduces the L-dopadose required for a therapeutically effective response and reduces theassociated side effects.

Even when L-dopa and carbidopa are co-administered, however, it isdifficult to consistently maintain the desired dopamine levels in thebrain due to the relatively short half-life of L-dopa in plasma. Inaddition, the tolerance of many patients to variability in dopaminelevels in the brain decreases as the disease progresses. One approachthat has been effective in reducing variability of dopamine levels isthe continuous intestinal delivery of an adjustable dose of anL-dopa/carbidopa gel known by its commercial name, DuoDopa®. DuoDopa® isa suspension of L-dopa/carbidopa monohydrate (4:1 ratio of L-dopa tocarbidopa monohydrate) in an aqueous gel. The gel is delivered to theproximal small intestine through a jejunal tube inserted through apercutaneous endoscopic gastrostomy port. DuoDopa® is packaged indisposable drug reservoirs (“DDRs”) and continuously administered via asoftware-controlled ambulatory infusion pump. Although L-dopa andcarbidopa have been co-administered to treat Parkinson's disease forseveral decades, a pharmaceutical composition suitable for use in anewer generation of lighter, smaller infusion pumps that deliver gelcompositions to the intestine is not currently commercially available.

The current composition of the DuoDopa® L-dopa/carbidopa intestinal gelis a gel for continuous intestinal administration. For long-termadministration, the gel is administered with a portable pump directlyinto the duodenum or upper jejunum via a percutaneous endoscopicgastrostomy tube with an inner intestinal/jejunal tube. Each 1 ml ofDuodopa® contains 20 mg levodopa and 5 mg carbidopa monohydrate. Despitethe current commercial success of DuoDopa®, the product is subject tolimitations in product preparation, including (1) risk of sedimentationof drug particles during storage and administration, (2) chemicalinstability of carbidopa, which leads to hydrazine formation.

Accordingly, there is a continuing need for improved formulations andmethods that can provide continuous and consistent dopamine levels inthe brain to effectively treat movement disorders such as Parkinson'sdisease. The present disclosure provides such improved formulations andmethods.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a levodopa active agent and a carbidopa activeagent for intraduodenal administration wherein the levodopa active agentis provided in an amount of about 4 weight/weight percent (w/w %) of thecomposition and carbidopa (e.g., carbidopa monohydrate) is provided inan amount of about 1 weight/weight percent of the composition whereinthe levodopa and carbidopa are suspended in an aqueous carrier. Thepharmaceutical composition has a desired viscosity suitable for storageunder refrigerated conditions and/or delivery (e.g., delivered via apump) at room temperature (e.g., ˜20° C. to ˜25° C.).

In another aspect, the present disclosure relates to a method oftreating Parkinson's disease in a patient in need thereof, wherein themethod comprises administering to the patient a pharmaceuticalcomposition comprising a levodopa active agent and a carbidopa activeagent for intraduodenal administration wherein the levodopa active agentand carbidopa active agent (e.g., carbidopa monohydrate) are provided inan amount of from about 4 weight/weight percent and 1 weight/weightpercent of the composition, respectively, suspended in an aqueouscarrier. The pharmaceutical composition has a desired viscosity suitablefor storage under refrigerated conditions and/or delivery (e.g.,delivered via a pump) at room temperature (e.g., ˜20° C. to ˜25° C.).

In another aspect, the present disclosure relates to methods ofmanufacturing a pharmaceutical composition of the invention, inparticular a high concentration pharmaceutical composition as disclosed,for example, in Example 1 and FIG. 1 below.

These and additional embodiments of the invention are further describedherein.

Further benefits of the present disclosure will be apparent to oneskilled in the art from reading this patent application. The embodimentsof the disclosure described in the following paragraphs are intended toillustrate the invention and should not be deemed to narrow the scope ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a manufacturing process flowchart for producing an exemplarypharmaceutical formulation of the invention.

FIG. 2 shows the L-Dopa blood level time-concentration profile inmini-pigs of an exemplary pharmaceutical composition of the invention asagainst two comparators, all given in a six-hour continuous infusion.

FIG. 3 shows the carbidopa blood level time-concentration profile inmini-pigs of an exemplary pharmaceutical composition of the invention asagainst two comparators, all given in a six-hour continuous infusion.

FIG. 4 shows average levodopa plasma concentrations in 12 human subjectsat various time points post administration.

FIG. 5 shows average carbidopa plasma concentrations in 12 humansubjects at various time points post administration.

FIG. 6 shows the dissolution rate at which levodopa and carbidopadissolve in a pH 4.5 media.

FIG. 7 shows the dissolution rate at which levodopa and carbidopadissolve in a pH 6.8 media.

FIG. 8 charts the decomposition of low and high concentration gelformulations into 3,4-dihydroxyphenylacetone (DHPA) over the course of15 weeks storage at 2-8° C.

FIG. 9 charts the decomposition of low and high concentration gelformulations into 2-methyl-3-(3,4-dihydroxyphenyl) propanoic acid(DHPPA) over the course of 15 weeks storage at 2-8° C.

FIG. 10 charts the decomposition of low and high concentration gelformulations into hydrazine over the course of 15 weeks storage at 2-8°C.

FIG. 11 shows the effects of oxygen scavengers in different packages onthe accumulation of DHPA (panel A) and DHPPA (panel B) degradationproducts. The abbreviations in the legend have the followingsignifications: 1×=2 w/w % levodopa, 0.5 w/w % carbidopa; 2×=4 w/w %levodopa, 1.0 w/w % carbidopa; EVA=container closure bag made fromEVA/EVOH/EVA material; Smiths=PVC bag used in Smiths Medical cassettereservoir; OW+Scav=with oxygen scavenger inside overwrapped aluminumfoil pouch.

DETAILED DESCRIPTION OF THE INVENTION

This written description uses examples to disclose the invention,including the best mode, and also to enable any person skilled in theart to practice the invention, including making and using any of thedisclosed pharmaceutical compositions, kits, pharmaceutical dosageforms, and performing any of the disclosed methods or processes. Thepatentable scope of the invention is defined by the claims, and mayinclude other examples that occur to those skilled in the art. Suchother examples are intended to be within the scope of the claims if theyhave elements that do not differ from the literal language of theclaims, or if they include equivalent elements.

I. DEFINITIONS

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition 15 to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “and/or” as used in a phrase such as “A and/or B” herein isintended to include “A and B”, “A or B”, “A”, and “B”.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

The terms “improve” and “improving” have their plain and ordinarymeaning to one skilled in the art of pharmaceutical or medical sciencesand specifically include ameliorating the effects of Parkinson'sdisease, or decreasing or lessening a symptom or side effect ofParkinson's disease.

The term “patient” includes mammals and humans, particularly humans.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” refers to any and all solvents, dispersion media,preservatives, antioxidants, coatings, isotonic and absorption delayingagents, and the like, that are compatible with pharmaceuticaladministration. The term “aqueous carrier” refers to a pharmaceuticallyacceptable carrier in which the solvent is water.

The term “pharmaceutically acceptable salt” refers to a salt of acompound that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methyl-bicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; and (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,dicyclohexylamine, and the like.

The terms “reduce” and “reducing” have their plain and ordinary meaningsto one skilled in the art of pharmaceutical or medical sciences andspecifically include diminishing or decreasing the number ofoccurrences, the duration, or the intensity, of a Parkinson's diseasesymptom or side effect, such as dyskinesias or hallucinations.

The term “therapeutically effective amount” means an amount of acompound that, when administered to a patient suffering from orsusceptible to Parkinson's disease or an associated condition issufficient, either alone or in combination with additional therapies, toeffect treatment for Parkinson's disease or the associated condition.The “therapeutically effective amount” will vary depending, for example,on the compound, pharmaceutical composition or pharmaceutical dosageform, the condition treated and its severity, and the age and weight ofthe patient to be treated.

The terms “treat” and “treating” have their plain and ordinary meaningto one skilled in the art of pharmaceutical or medical sciences andspecifically include improving the quality of life or reducing thesymptoms or side effects of Parkinson's disease.

II. PHARMACEUTICAL COMPOSITIONS

The present disclosure relates to a pharmaceutical compositioncomprising a levodopa active agent and a carbidopa active agent forintraduodenal administration wherein the levodopa active agent andcarbidopa active agent are present in a therapeutically effective amountsuspended in an aqueous carrier, characterized in that the levodopaactive agent and the carbidopa active agent in the carrier has a highshear viscosity of no more than about 4500 cps at room temperature(e.g., ˜20° C. to ˜25° C., such as ˜22° C.) and a low shear viscosity ofno less than about 45000 cps under refrigerated storage conditions (forexample, at about 2° C. to about 8° C., such as 5° C.). Additionally oralternatively, the pharmaceutical composition—i.e., the aqueous carrierwith the levodopa active agent and carbidopa active agent suspendedtherein—can have a ratio of low shear viscosity to high shear viscosityof not less than about 10. In particular, the aqueous carrier with thelevodopa active agent and carbidopa active agent suspended therein canhave a high shear viscosity of no more than about 4500 cps at roomtemperature (e.g., ˜20° C. to ˜25° C., such as ˜22° C.) and a low shearviscosity of no less than about 45000 cps under refrigerated storageconditions (for example, at about 2° C. to about 8° C., such as 5° C.)and a ratio of low shear viscosity to high shear viscosity of not lessthan about 10. The pharmaceutical compositions may have theaforementioned low shear viscosity and high shear viscosity throughoutshelf life. As used herein, “shelf life” includes at least about 2weeks, for example, at least about 5 weeks, at least about 10 weeks, atleast about 15 weeks, or at least about 20 weeks. For example, thepharmaceutical composition can have a high shear viscosity of about4300-4400 cps (at ˜22° C.) and a low shear viscosity of about 49600 cps(at ˜5° C.) throughout its shelf life.

Both low shear and high shear viscosity can be measured by routinemethods known in the art. For purposes of measuring viscosity of thecompositions and formulations disclosed herein, low shear viscosityshould be measured in a sample of ˜9 mL at a temperature of ˜5° C. and ashear rate of ˜0.1 sec⁻¹. If the viscosity is measured in, e.g., aBROOKFIELD Model LV viscometer (for example in sample chamber SC4-13Rwith temperature probe and water jacket assembly SC4-45Y), then the testshould be conducted with an SC4-31 model spindle. Where other equipmentis used, a spindle of corresponding dimensions and specifications can besubstituted accordingly.

High sheer viscosity should be measured in a sample of ˜16 mL at atemperature of ˜22° C. and a shear rate of ˜24.1 sec⁻¹. If the viscosityis measured in, e.g., a BOHLIN model 88 BV rotational viscometer, thenthe test should be conducted with a C25 cylinder/spindle system. Whereother equipment is used, a spindle of corresponding dimensions andspecifications can be substituted accordingly.

In various aspects, the therapeutically effective amount of a levodopaactive agent and a carbidopa active agent (e.g., carbidopa monohydrate)present in the pharmaceutical composition may be about 4.0 and 1.0weight/weight percent of the composition, respectively.

As previously noted, the inherently low aqueous solubility of L-dopa andcarbidopa at physiologically acceptable pH for infusion presents asignificant technical challenge to the development of improvedpharmaceutical compositions and methods of treatment. Such challengesinclude, for example, difficulties in achieving formulation stabilitywithin the required pH limitations. These challenges are furthercomplicated by the requirement that the pharmaceutical compositions andmethods of treatment provide pharmacokinetically-appropriate andpharmacokinetically-consistent control of dopamine levels in thepatient's brain.

In one embodiment, the pharmaceutical composition comprises a levodopaactive agent in an amount of about 4.0 weight/weight percent of thetotal composition; a carbidopa active agent (e.g., carbidopamonohydrate) in an amount of about 1.0 weight/weight percent of thetotal composition; at least one suspending agent; and a liquid vehicle(for example, water). In various embodiments, the liquid vehicle canmake up from about zero weight/weight percent to about 95 weight/weightpercent of the total composition, for example from about 10weight/weight percent to about 70 weight/weight percent, or from about40 weight/weight percent to about 60 weight/weight percent of the totalcomposition.

In one embodiment, the levodopa active agent is levodopa andpharmaceutically acceptable salts or hydrates thereof, such as levodopamonohydrate. Levodopa is preferably present in the composition in anamount of from about 1.0 to 5.0 weight/weight percent in the totalcomposition. In a preferred embodiment the pharmaceutical compositioncomprises about 4.0 weight/weight percent of a levodopa active agent. Inone embodiment, the levodopa active agent can be processed intomicroparticles or microspheres or the like, for example as described inExample 1 below, for inclusion in the present pharmaceuticalcompositions.

In one embodiment, the carbidopa active agent is carbidopa andpharmaceutically acceptable salts or hydrates thereof, such as carbidopamonohydrate. The carbidopa active agent is preferably present in thecomposition in an amount of from about 0.25 to 1.25 weight/weightpercent in the total composition. In a preferred embodiment thepharmaceutical composition comprises about 1.0 weight/weight percent ofa carbidopa active agent. The preferred form of carbidopa active agentto be administered is carbidopa monohydrate. In one embodiment, thecarbidopa active agent can be processed into microparticles ormicrospheres or the like, for example as described in Example 1 below,for inclusion in the present pharmaceutical compositions.

The levodopa active agent and carbidopa active agent may be present inthe pharmaceutical composition in any suitable ratio, for example, theratio of levodopa active agent to carbidopa active agent (e.g.,carbidopa monohydrate) in the present pharmaceutical compositions may beabout 4:1. For example, the pharmaceutical composition can compriseabout 4 weight/weight percent of levodopa active agent and 1weight/weight percent carbidopa active agent (e.g., carbidopamonohydrate). In one embodiment, the pharmaceutical compositioncomprises a liquid or viscous liquid comprising about 200 mg levodopaand about 50 mg carbidopa (e.g., carbidopa monohydrate) per each 5.0 mLvolume. In one embodiment, the levodopa active agent and the carbidopaactive agent are processed into microparticles or microspheres or thelike, for example as described in Example 1 below, for inclusion in thepresent pharmaceutical compositions.

The ratio of levodopa active agent, or of the combination of levodopaactive agent to carbidopa active agent, to a suspending agent is fromabout 3 to about 1 w/w % to about 1 to about 30 w/w %, with a generallypreferred range from about 2 to about 1 w/w % to about 1 to about 10 w/w%. Such readily available suspending agents are well known in the artand can include polymer-based suspending agents, such as, but notlimited to, carbohydrate-based suspending agents and acrylic acid-basedpolymers (e.g., Carbomer, Carbopol®). Exemplary carbohydrate-basedsuspending agents include, but are not limited tohydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethylcellulose (NaCMC). Acrylic acid-based polymers may be cross-linked, forexample, cross-linked with polyalkenyl ethers or divinyl glycol. Inparticular, the suspending agent may be sodium carboxymethyl cellulose(NaCMC) or Carbopol.

For the present compositions, one or more suspending agents can be usedto obtain the ratios of levodopa active agent, or of the combination oflevodopa active agent to carbidopa active agent, to suspending agent asset forth above.

However, when a surfactant is used, it may be best to add the surfactantor surfactants following addition of levodopa active agent and carbidopaactive agent and suspending agent as taught herein.

It should be understood that each component comprising the compositionsof the present invention must be pharmaceutically acceptable andutilized in a non-toxic concentration.

In one embodiment, the pharmaceutical composition is a viscous liquidcomposition. In one aspect, the pharmaceutical composition compriseswater and is suitable for infusion.

In another embodiment, the pharmaceutical composition is an aqueouspharmaceutical composition having a levodopa active agent concentrationof at least about 5 mg/mL. In one aspect, the levodopa active agentconcentration is at least about 10 mg/mL. In another aspect, thelevodopa active agent concentration is at least about 20 mg/mL. Inanother aspect, the levodopa active agent concentration is at leastabout 30 mg/mL. In another aspect, the levodopa active agentconcentration is at least about 35 mg/mL. In another aspect, thelevodopa active agent concentration is at least about 40 mg/mL. Inanother aspect, the levodopa active agent concentration is at leastabout 45 mg/mL. In another aspect, the levodopa active agentconcentration is at least about 50 mg/mL. In another aspect, thelevodopa active agent concentration is at least about 100 mg/mL. Inanother aspect, the levodopa active agent concentration is at leastabout 150 mg/mL. In another aspect, the levodopa active agentconcentration is at least about 200 mg/mL.

In another embodiment, the pharmaceutical composition is an aqueouspharmaceutical composition having a carbidopa active agent (e.g.,carbidopa monohydrate) concentration of at least about 5 mg/mL. In oneaspect, the carbidopa active agent concentration is at least about 10mg/mL. In another aspect, the carbidopa active agent concentration is atleast about 20 mg/mL. In another aspect, the carbidopa active agentconcentration is at least about 30 mg/mL. In another aspect, thecarbidopa active agent concentration is at least about 50 mg/mL. Inanother aspect, the carbidopa active agent concentration is at leastabout 100 mg/mL. In another aspect, the carbidopa active agentconcentration is at least about 150 mg/mL. In another aspect, the activeagent carbidopa concentration is at least about 200 mg/mL.

The pharmaceutical compositions of the present disclosure optionallycomprise one or more additional pharmaceutically acceptable excipients.The term “excipient” refers to any substance, not itself a therapeuticagent, used as a carrier or vehicle for delivery of a therapeutic agentto a subject or added to a pharmaceutical composition to improve itshandling or storage properties or to permit or facilitate formation of aunit dose of the composition.

Excipients include, for example, antioxidants, agents to adjust the pHand osmolarity, preservatives, thickening agents, colorants, bufferingagents, bacteriostats, and stabilizers. A given excipient, if present,generally will be present in an amount of about 0.001% to about 95%,about 0.01% to about 80%, about 0.02% to about 25%, or about 0.3% toabout 10%, by weight.

In one embodiment, the pharmaceutical compositions optionally comprisean antioxidant. Suitable antioxidants for use in the pharmaceuticalcompositions include, for example, butylated hydroxytoluene, butylatedhydroxyanisole, potassium metabisulfite, cysteine, and the like.

In one embodiment, the pharmaceutical compositions optionally comprise abuffering agent. Buffering agents include agents that reduce pH changes.Suitable classes of buffering agents for use in various embodiments ofthe present invention comprise a salt of a Group IA metal including, forexample, a bicarbonate salt of a Group IA metal, a carbonate salt of aGroup IA metal, an alkaline or alkali earth metal buffering agent, analuminum buffering agent, a calcium buffering agent, a sodium bufferingagent, or a magnesium buffering agent. Suitable buffering agents furtherinclude carbonates, phosphates, bicarbonates, citrates, borates,acetates, phthalates, tartrates, succinates of any of the foregoing, forexample, sodium or potassium phosphate, citrate, borate, acetate,bicarbonate and carbonate.

In one embodiment, the composition has a pH from about 3.5 to about 8.In one aspect, the pH is from about 3.5 to about 7.5. In another aspect,the pH is from about 4.0 to about 7.5. In another aspect, the pH is fromabout 5.0 to about 7.5. In another aspect, the pH is from about 5.5 toabout 7.5. In another aspect, the pH is from about 6.0 to about 7.5.

In various embodiments, the pharmaceutical composition may be present ina container. Suitable containers include containers (e.g., a bag) withlower oxygen permeability (e.g., oxygen transmission rate of ˜0.95cc/(100 in²*day)) or which are oxygen impermeable. These low oxygenpermeability barriers may be incorporated into the primary container ofa secondary outer container. Non-limiting examples of suitablecontainers include DDR (Disposable Drug Reservoirs) bags, such as anEVA/EVOH/EVA bag.

In still other embodiments, the present disclosure relates to aready-to-use vial or cartridge or container or enclosure suitable forliquid pharmaceutical dosage formulation containment. Such container mayserve the function of holding a liquid formulation containing one ormore active ingredients. The vials can also serve as storage for powderforms of the active ingredients such that the vial can be in a ready touse format wherein reconstitution with an aqueous vehicle results in aready-to-withdraw or ready-to-load injection to the patient.

In another embodiment, a pharmaceutical dosage form is provided. Thepharmaceutical dosage form may comprise the pharmaceutical compositiondescribed herein in a DDR having an oxygen impermeable enclosuredisposed therein, wherein the oxygen impermeable enclosure is purgedwith an inert gas (e.g., N₂). An oxygen scavenger (e.g., ferrous ornon-ferrous based, canister or sachet) may also be added. Thepharmaceutical dosage form may suitable for use in a continuous infusionpump capable of delivering the composition in a therapeuticallyeffective manner. A suitable oxygen impermeable enclosure can include,for example, a foil bag or a bag having an EVA-EVOH film layer.

III. METHODS OF PREPARING A PHARMACEUTICAL COMPOSITION

The present disclosure further relates to methods of preparing thepharmaceutical compositions described herein. In various aspects, themethods of preparing the pharmaceutical composition describe herein cancomprise providing a levodopa active agent and a carbidopa active agentin suitable amounts so that the levodopa active agent and carbidopaactive agent are present in therapeutically effective amounts in thepharmaceutical composition. The levodopa active agent and carbidopaactive agent may be added to water to produce a slurry. The slurry maybe added to one or more suspending agents (e.g., NaCMC) as describedherein to form a suspension. The suspension may or may not undergo N₂sparging to reduce the oxygen level. Particularly, the suspension may besubjected to N₂ sparging. Optionally, the suspension may be degassed toremove any entrapped nitrogen or air from the suspension. The suspensionmay then be loaded into lower oxygen permeability or oxygen impermeablecontainers as described herein. Optionally, an oxygen scavenger may beadded to the suspension as well. The combination of N₂ sparging of thesuspension and use of lower oxygen permeability containersadvantageously can result in a pharmaceutical composition with increasedchemical stability by reducing both the initial solubilized O₂ presentin the composition and the amount of O₂ ingress into the compositionduring storage.

Additionally, when the suspension is subjected to N₂ sparging and/or thecontainer has low oxygen permeability, the pharmaceutical compositionmay not experience degradation into DHPA at a rate faster than 0.04 w/w% per week of refrigerated storage conditions. (The percent is relativeto the label amount of carbidopa.) Additionally or alternatively, whenthe suspension is subjected to N₂ sparging and/or the container has lowoxygen permeability, the pharmaceutical composition may not experiencedegradation into DHPPA at a rate faster than 0.04 w/w % per week ofrefrigerated storage conditions. (The percent is relative to the labelamount of carbidopa.) Additionally or alternatively, when the suspensionis subjected to N₂ sparging and/or the container has low oxygenpermeability, the pharmaceutical composition may not degrade producinghydrazine at a rate faster than 0.6 μg/g per week per week ofrefrigerated storage, where μg/g denotes μg of hydrazine per gram ofgel-suspension.

In various aspects, the levodopa active agent (e.g., prior to formingthe suspension) may have a particle size distribution where:

-   -   (i) D50 may be less than or equal to about 5 μm, less than or        equal to about 3 μm, or less than or equal to about 1 μm;    -   (ii) D90 may be less than or equal to about 11 μm, less than or        equal to about 9 μm, less than or equal to about 7 μm, less than        or equal to about 5 μm or less than or equal to about 3 μm; and    -   (iii) D100 may be less than or equal less than or equal to about        22 μm, less than or equal to about 21 μm, less than or equal to        about 19 μm, less than or equal to about 17 μm, less than or        equal to about 15 μm, less than or equal to about 13 μm or less        than or equal to about 11 μm.        In particular, the levodopa active agent may have a particle        size distribution of: (i) D50 less than or equal to about 5        μm; (ii) D90 less than or equal to 11 μm; and (iii) D100 less        than or equal to 22 μm.

Additionally, the carbidopa active agent (e.g., prior to forming thesuspension) may have a particle size distribution where:

-   -   (i) D50 may be less than or equal to 3 μm;    -   (ii) D90 may be less than or equal to 7 μm, or less than or        equal to 5 μm; and    -   (iii) D100 may be less than or equal to 21 μm, less than or        equal to 19 μm, less than or equal to 17 μm, less than or equal        to 15 μm, less than or equal to 13 μm, less than or equal to 11        μm, less than or equal to 9 μm.        In particular, the carbidopa active agent may have a particle        size distribution of: (i) D50 less than or equal to about 3        μm; (ii) D90 less than or equal to 7 μm; and (iii) D100 less        than or equal to 21 μm. The levodopa active agent and/or the        carbidopa active may be milled or micronized to achieve such a        particle size distribution.

Advantageously, the levodopa active agent and the carbidopa active agentwith the above described particle size distributions may successfullyform a suspension and maintain physical stability of the suspensionthroughout the pharmaceutical composition's shelf life even when thelevodopa active agent and the carbidopa active agent are present athigher concentrations in the composition. For example, physicalstability may be maintained even when the pharmaceutical compositioncomprises about 4 weight/weight percent of levodopa active agent and 1weight/weight percent carbidopa active agent (e.g., carbidopamonohydrate).

In another embodiment, pharmaceutical compositions as described hereinprepared by the methods described herein are provided. In particular, alevodopa active agent and a carbidopa active agent may be provided insuitable amounts so that the levodopa active agent and carbidopa activeagent are present in therapeutically effective amounts in thepharmaceutical composition. The levodopa active agent and the carbidopaactive agent provided have a particle size distribution as describedabove. The levodopa active agent and carbidopa active agent are added towater to produce a slurry. The slurry is added to a suspending agent(e.g., NaCMC) as described herein or a mixture of suspending agents toform a suspension, and the suspension can undergo N₂ sparging to reducethe oxygen level. The suspension can be loaded into lower oxygenpermeability or oxygen impermeable containers as described herein.Optionally, an oxygen scavenger may be added to the suspension as well.

IV. METHODS OF TREATMENT

The present disclosure further relates to methods of treatingParkinson's disease and associated conditions comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising a high concentration levodopa active agent and carbidopaactive agent to a patient. A pharmaceutical composition comprising ahigh concentration levodopa active agent and carbidopa active agent cancomprise, for example, a liquid or viscous liquid comprising about 200mg levodopa and about 50 mg carbidopa monohydrate per each 5.0 mLvolume.

In one embodiment, the present disclosure relates to a method oftreating a condition in need of treatment, wherein the method comprisesadministering to the patient a therapeutically effective amount of apharmaceutical composition of the present disclosure.

In one embodiment, the condition treated by administering thepharmaceutical composition is Parkinson's disease.

In another embodiment, the condition treated by administering thepharmaceutical composition is impaired motor performance in a patientwith Parkinson's disease (i.e., a method of improving motor performancein a patient with Parkinson's disease).

In another embodiment, the pharmaceutical composition is administered totreat motor fluctuations in a patient with Parkinson's disease.

In another embodiment, the pharmaceutical composition is administered totreat dyskinesia in a patient with Parkinson's disease.

In another embodiment, the present pharmaceutical compositions areadministered via intestinal administration. They can be administered (or“infused”) directly into the intestine, such as the small intestine(e.g., duodenum or the jejunum) by a permanent tube inserted viapercutaneous endoscopic gastrostomy, for example, with an outertransabdominal tube and an inner intestinal tube. In one aspect, thefirst compound and the second compound are administered via a tubeinserted by radiological gastrojejunostomy. In another aspect, thepresent pharmaceutical compositions are administered via a temporarynasoduodenal tube that is inserted into the patient, for example toinitially to determine if the patient responds favorably to thetreatment method before the permanent tube is inserted.

In embodiments where one or more of the present pharmaceuticalcompositions are administered via intestinal administration,administration can be carried out using a portable pump, such as thepump sold under the trade name, CADD-Legacy Duodopa® pump. Specifically,a cassette, pouch, vial or cartridge comprising the first compound andthe second compound can be attached to the pump to create the deliverysystem. The delivery system is then connected to the nasoduodenal tube,the transabdominal port, the duodenal tube, or the jejunum tube forintestinal administration.

In one embodiment, the method comprises administering one or more of thepresent pharmaceutical compositions to the patient substantiallycontinuously over a period of at least about 12 hours. In additionalaspects, the present pharmaceutical compositions can be administeredsubstantially continuously over a period of about 16 hours, about 24hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about5 days, about 6 days, about one week, or longer.

In one embodiment, the dosing of the present pharmaceutical compositionadministered to the patient is adjusted to optimize the clinicalresponse achieved by a patient, which means, for example, maximizing thefunctional ON-time during the day by minimizing the number and durationof OFF-time episodes (i.e., bradykinesia) and minimizing ON-time withdisabling dyskinesia.

In one embodiment, the daily dose of levodopa active agent administeredto the patient according to methods of the present disclosure may be,for example, about 20 to about 5000 mg, about 20 mg to about 4000 mg,about 20 mg to about 3000 mg, about 20 mg to about 2000 mg, or about 20mg to about 1000 mg per day. In various aspects, the patient mayreceive, for example, about: 20, 30, 40, 50, 60, 70, 80, 90, 100, 110,120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250,260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390,400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530,540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670,680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810,820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950,960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070,1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190,1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310,1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430,1440, 1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 1550,1560, 1570, 1580, 1590, 1600, 1610, 1620, 1630, 1640, 1650, 1660, 1670,1680, 1690, 1700, 1710, 1720, 1730, 1740, 1750, 1760, 1770, 1780, 1790,1800, 1810, 1820, 1830, 1840, 1850, 1860, 1870, 1880, 1890, 1900, 1910,1920, 1930, 1940, 1950, 1960, 1970, 1980, 1990, 2000, 2010, 2020, 2030,2040, 2050, 2060, 2070, 2080, 2090, 2100, 2110, 2120, 2130, 2140, 2150,2160, 2170, 2180, 2190, 2200, 2210, 2220, 2230, 2240, 2250, 2260, 2270,2280, 2290, 2300, 2310, 2320, 2330, 2340, 2350, 2360, 2370, 2380, 2390,2400, 2410, 2420, 2430, 2440, 2450, 2460, 2470, 2480, 2490, 2500, 2600,2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800,3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or5000 mg of levodopa active agent per day.

In one embodiment, the daily dose of the carbidopa active agentadministered to the patient according to methods of the presentdisclosure may be, for example, 0 to about 625 mg, 0 mg to about 500 mg,0 mg to about 375 mg, 0 mg to about 250 mg, or 0 mg to about 125 mg perday. In various aspects, the patient may receive, for example, about:20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170,180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310,320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450,460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590,600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730,740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870,880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010,1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130,1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, or1250 mg of carbidopa active agent per day.

In some embodiments, an amount of levodopa active agent and carbidopaactive agent are administered such that in combination they aresufficient to achieve an L-dopa plasma level in the patient of at leastabout 100 ng/mL. In one aspect, the L-dopa plasma level is at leastabout 200 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 200 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 300 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 400 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 500 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 600 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 700 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 800 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 900 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 1,000 ng/mL. In another aspect, the L-dopa plasma level is atleast about 1,500 ng/mL. In another aspect, the L-dopa plasma level isat least about 2,000 ng/mL. In another aspect, the L-dopa plasma levelis at least about 3,000 ng/mL. In another aspect, the L-dopa plasmalevel is at least about 4,000 ng/mL. In another aspect, the L-dopaplasma level is at least about 5,000 ng/mL.

In some embodiments, an amount of the levodopa active agent andcarbidopa active agent are administered such that in combination theyare sufficient to achieve an L-dopa plasma level from about 10 ng/mL toabout 8,000 ng/mL. In one aspect, the L-dopa plasma level is from about25 ng/mL to about 6,000 ng/mL. In another aspect, the L-dopa plasmalevel is from about 50 ng/mL to about 4,000 ng/mL. In another aspect,the L-dopa plasma level is from about 100 ng/mL to about 2,000 ng/mL. Inanother aspect, the L-dopa plasma level is from about 25 ng/mL to about1,200 ng/mL. In another aspect, the L-dopa plasma level is from about 10ng/mL to about 500 ng/mL. In another aspect, the L-dopa plasma level isfrom about 25 ng/mL to about 500 ng/mL.

In some embodiments, the above-described L-dopa concentration ranges aremaintained for at least about: a 1 hour interval, a 2 hour interval, a 3hour interval, a 4 hour interval, a 5 hour interval, a 6 hour interval,a 7 hour interval, an 8 hour interval, a 9 hour interval, a 10 hourinterval, an 11 hour interval, a 12 hour interval, an 18 hour interval,or a 24 hour interval.

In some embodiments, an amount of the levodopa active agent andcarbidopa active agent are administered such that in combination theyare sufficient to maintain a carbidopa plasma level less than about 500ng/mL. In one aspect, the carbidopa plasma level is less than about 250ng/mL. In another aspect, the carbidopa plasma level is less than about100 ng/mL. In another aspect, the carbidopa plasma level is less thanabout 50 ng/mL. In another aspect, the carbidopa plasma level is lessthan about 25 ng/mL.

In some embodiments, an amount of the levodopa active agent andcarbidopa active agent are administered such that in combination theyare sufficient to maintain a carbidopa plasma level from about 1 toabout 10 ng/mL. In one aspect, the carbidopa plasma level is from about1 to about 25 ng/mL. In another aspect, the carbidopa plasma level isfrom about 1 to about 50 ng/mL. In another aspect, the carbidopa plasmalevel is from about 1 to about 100 ng/mL. In another aspect, thecarbidopa plasma level is from about 1 to about 250 ng/mL. In anotheraspect, the carbidopa plasma level is from about 5 to about 250 ng/mL.In another aspect, the carbidopa plasma level is from about 5 to about100 ng/mL. In another aspect, the carbidopa plasma level is from about10 to about 250 ng/mL. In another aspect, the carbidopa plasma level isfrom about 10 to about 100 ng/mL. In another aspect, the carbidopaplasma level is from about 25 to about 250 ng/mL. In another aspect, thecarbidopa plasma level is from about 25 to about 100 ng/mL.

In some embodiments, the above-described carbidopa concentration rangesare maintained for at least about: a 1 hour interval, a 2 hour interval,a 3 hour interval, a 4 hour interval, a 5 hour interval, a 6 hourinterval, a 7 hour interval, an 8 hour interval, a 9 hour interval, a 10hour interval, an 11 hour interval, a 12 hour interval, an 18 hourinterval, or a 24 hour interval.

In additional embodiments, the levodopa active agent and the carbidopaactive agent administered may have a particle size distribution of asdescribed above.

In various embodiments, the pharmaceutical composition may be present ina container as described above and prior to administration to thepatient, the gel-suspension may or may not be subjected to N₂ sparging.When the gel-suspension is subjected to N₂ sparging and the containerhas low oxygen permeability, the pharmaceutical composition may notexperience degradation producing DHPA at a rate faster than 0.04 w/w %per week of refrigerated storage. (The percent is relative to the labelamount of carbidopa.) Additionally or alternatively, when the containeris subjected to N₂ sparging, the pharmaceutical composition may notexperience degradation producing DHPPA at a rate faster than 0.04 w/w %per week of refrigerated storage. (The percent is relative to the labelamount of carbidopa.) Additionally or alternatively, when the containeris subjected to N₂ sparging, the pharmaceutical composition may notdegrade producing hydrazine at a rate faster than 0.6 μg/g per week ofrefrigerated storage, where μg/g denotes μg of hydrazine per gram ofgel-suspension.

V. CO-ADMINISTRATION OF ADDITIONAL THERAPEUTIC AGENTS

The methods of treatment of the present disclosure optionally canfurther comprise administration of one or more therapeutic agents forthe treatment of Parkinson's disease in addition to administration ofthe levodopa active agent and carbidopa active agent. In one embodiment,the additional therapeutic agent(s) is selected from the groupconsisting of decarboxylase inhibitors other than a carbidopa activeagent (e.g., benserazide), catechol-0-methyl transferase (“COMT”)inhibitors (e.g., entacapone and tolcapone), and monoamine oxidase A(“MAO-A”) or monoamine oxidase B (“MAO-B”) inhibitors (e.g.,moclobemide, rasagiline, selegiline, and safinamide). In one aspect, theadditional therapeutic agent(s) is selected from the group consisting ofdecarboxylase inhibitors other than a carbidopa active agent. In anotheraspect, the additional therapeutic agent(s) is selected from the groupconsisting of COMT inhibitors. In another aspect, the additionaltherapeutic agent(s) is selected from the group consisting of MAO-Ainhibitors. In another aspect, the additional therapeutic agent(s) isselected from the group consisting of MAO-B inhibitors.

In a similar manner, the pharmaceutical compositions of the presentdisclosure optionally can further comprise one or more additionaltherapeutic agents for the treatment of Parkinson's disease as describedabove.

VI. KITS

The present disclosure also relates to kits comprising one or morepharmaceutical dosage forms comprising a carbidopa active agent; kitscomprising one or more pharmaceutical dosage forms comprising a levodopaactive agent; and kits comprising one or more pharmaceutical dosageforms comprising both a levodopa active agent and carbidopa activeagent. In the kit, the pharmaceutical dosage forms may be present,separately or together, in a lower O₂ permeability bag. Thepharmaceutical dosage forms may comprise a high concentration of alevodopa active agent and a carbidopa active agent, for example, alevodopa active agent in an amount of about 4.0 weight/weight percent ofthe total composition; and a carbidopa monohydrate active agent in anamount of about 1.0 weight/weight percent of the total composition. Thekit optionally can comprise one or more additional therapeutic agentsand/or instructions, for example, instructions for using the kit totreat a patient having Parkinson's disease or an associated condition.

VII. EXAMPLES

The following non-limiting examples are provided to further illustratethe present disclosure. Abbreviations used in the examples below includethe following:

-   -   “Cmax” means maximum observed plasma concentration.    -   “Tmax” means time to maximum observed plasma concentration.    -   “AUC” means area under the plasma concentration-time curve.    -   “t_(1/2)” means biological half-life, i.e., the time required        for half the quantity of a drug or other substance administered        to a living organism to be metabolized or eliminated by normal        biological processes.

Example 1: Preparation of Pharmaceutical Composition

A high concentration (“HC”) levodopa active agent/carbidopa active agentpharmaceutical composition was prepared as shown in FIG. 1 and asdescribed below:

1.1 Gel Preparation

Pre-work was performed in the lab to establish the ratio of NaCMC 700 toNaCMC 2000 needed to achieve a certain viscosity. The viscosity wasmeasured with a rotational viscometer at two points: 22° C. at 24.1 1/s(also called the “high shear viscosity”); and at 5° C. at 0.1 1/s (alsocalled the “low shear viscosity”). The proper amounts of NaCMC 2000 andNaCMC 700 were then dispensed and added to a hopper, after which theNaCMC was fed into the homogenizer tank and mixed at a high shear. Thegel was then degassed and visually inspected to ensure that the NaCMCdissolved. This was also the time that the gel is sampled for viscositymeasurements.

1.2 Gel Sparging

Gel was sparged with nitrogen to remove the majority of oxygen prior toadding the API (Levodopa and Carbidopa). Oxygen concentration wasmonitored throughout the process via an inline oxygen probe.

1.3 First Slurry Preparation

Half of Levodopa and Carbidopa was added to water in a separate vesseland was mixed using one overhead impeller and one bottom drivenimpeller. This method is considered low shear. Alternatively theoverhead impeller can be replaced with a homogenizer for achieving highshear mixing. The slurry was used to wet and delump the API. After theprocess was finished, the slurry was transferred to the homogenizertank.

1.4 Gel Suspension Preparation

This is where the API from the slurry and the NaCMC gel was mixed, underhigh shear, to achieve a homogeneous suspension. Nitrogen was spargedinto the tank to reduce the oxygen level that was initially introducedwith the slurry transfer.

1.5 Second Slurry Preparation

The other half of Levodopa and Carbidopa was added to water and mixedsimilar to the process in step 1.3.

1.6 Gel Suspension Preparation

The API from the second slurry was mixed with the rest of the gelsuspension at the same conditions as in step 1.4. Nitrogen was spargedinto the tank to reduce the oxygen level that was initially introducedwith the slurry transfer.

1.7 Degassing

The gel suspension was degassed to remove any entrapped nitrogen or airfrom the gel.

1.8 Filling

The filling lines were first flushed with nitrogen before gel suspensionwas pushed through. 55-61 g of gel suspension was filled into disposabledrug reservoirs (DDRs). Fill weight was checked at routine intervals viaa balance. Oxygen reading was taken at the filling nozzle (for the twocase studies, the reading was taken at the discharge end).

1.9 Packaging

DDRs were labeled and packaged into a kit that holds 7 DDRs. The kitprotects the formulation from light. The kits were then sent to thefreezer.

TABLE 1 Formulation of High Concentration (HC) and Low Concentration(LC) Pharmaceutical Composition Component HC w/w % LC w/w % LevodopaMicronized 4 2 Carbidopa Monohydrate 1 0.5 Micronized NaCMC 2000 2.92*2.92* NaCMC 700 Purified Water 92.08 94.58 *Represents total NaCMC. Theratio of one NaCMC grade to the other can be varied to achieve thedesired viscosity. **Density of HC formulation was approximately 1.03g/ml and LC formulation is approximately 1.02 g/ml

TABLE 2 LC Specifications and HC Tentative Ranges for Drug Product andAPI Attributes HC Tentative Drug Product Attributes LC Specs Range HighShear Viscosity 2000-3500 cps ≤4500 cps (22° C. and 24.1 1/s) Low ShearViscosity >21000 cps >45000 cps (5° C. and 0.1 1/s) pH 5.5-7.5 OxygenConcentration Ambient Low Batch Size 500 Kg

Example 2: High Concentration Pharmaceutical Composition Stability

2.1—A high concentration (HC) formulation was made on the commercialscale equipment to improve the nitrogen sparging process time and mixingefficiency. The overall manufacturing process was the same as inExample 1. A high viscosity was chosen, relative to the HC formulationviscosity range, to ensure good physical stability. The batch was filledinto prototype DDR (Disposable Drug Reservoirs) bags (without thehousing) and placed on stability. The bags are made with a 0.3 mm thickEVA/EVOH/EVA multilayer film. This batch maintained its chemical andphysical stability throughout the 15 week stability study.

TABLE 3 Raw Material and Finished Material Attributes SuspensionAttributes Value High Shear Viscosity (24.1 1/s, 22° C.) 43000 cps LowShear Viscosity (0.1 1/s, 5° C.) 49600 cps pH 6.4* Oxygen Concentration0.45* mg/L Batch Size 500 Kg *Values were measured in process

2.2—Analytical Results

Batch Content Uniformity—100 mL of the pharmaceutical composition wasfilled into cassettes at the beginning, middle, and end of the fillingrun which represents bottom, middle, and top of the tank, respectively.These cassettes were then assayed and the results represent the contentuniformity of the batch.

TABLE 4 Batch Content Uniformity Results (API concentration) CassettesLevodopa % Carbidopa % Beginning 1 94.9 94.6 Beginning 2 101.9 101.6Beginning 3 99.5 99.0 Beginning 4 98.7 98.4 Beginning 5 99.7 99.4 Middle1 101.8 101.6 Middle 2 99.7 99.3 Middle 3 99.1 99.0 Middle 4 96.0 95.8Middle 5 101.2 100.9 End 1 101.3 101.0 End 2 101.6 101.4 End 3 101.6101.3 End 4 101.7 101.5 End 5 101.8 101.6

2.3—Formulation Attributes on Stability

Filled DDR bags were frozen and stored at −20° C. after manufacture.Bags for testing were then placed at 5° C. for a 15 week stabilitystudy. Samples were evaluated at 0, 8, and 15 weeks. In addition, aportion of the samples were subsequently placed at 30° C. in 75%relative humidity (% RH), after they spent either 8 or 15 weeks at 5°C., with testing at 24 and 48 hours. Assay, impurities, pH, andviscosity were all tested. Results are summarized in Table 5 below.

TABLE 5 Assay, Impurities, pH, and Viscosity Throughout a 15 WeeksStability Study Levodopa Carbidopa % DHPA per % DHPPA per ConditionAssay (%) Assay (%) Carbidopa Carbidopa 5° C.: 0 weeks 102.3 100.5 0.140.06 5° C.: 8 weeks 104.3 102.7 0.44 0.42 5° C.: 8 weeks 102.4 100.90.46 0.41 30° C.: 24 hrs 5° C.: 8 weeks 103 101.4 0.50 0.47 30° C.: 48hrs 5° C.: 15 weeks 102.1 99.8 0.60 0.60 5° C.: 15 weeks 102.5 100 0.740.80 30° C.: 24 hrs 5° C.: 15 weeks 102.2 99.7 0.74 0.79 30° C.: 48 hrsViscosity (cps) Viscosity (cps) Hydrazine (μg) at 22° C. and at 5° C.and Condition per gel (g) pH 24.1 sec⁻¹ 0.1 sec⁻¹ 5° C.: 0 weeks 2.106.4 4400 49600 5° C.: 8 weeks 6.63 6.4 4500 57400 5° C.: 8 weeks 7.436.3 4500 59900 30° C.: 24 hrs 5° C.: 8 weeks 9.90 6.4 4500 54200 30° C.:48 hrs 5° C.: 15 weeks 9.20 6.3 4400 58300 5° C.: 15 weeks 10.90 6.34400 59000 30° C.: 24 hrs 5° C.: 15 weeks 11.10 6.3 4500 55200 30° C.:48 hrs

2.4—Uniformity of Dispensed Content of Samples on Stability

The uniformity of dispensed content (UDC) method was used to obtain APIconcentration in the gel as it is dosed. This simulates what a patientwould be receiving per every 5 g of gel delivered by the pump, andensures that a patient will be receiving consistent amounts of drugthroughout the consumption of one DDR. The test was performed at eachtime point throughout the 15 week stability. Particle size distributionsof the APIs used for the study were within the particle size limitsmentioned herein. Results are summarized in Tables 6 (levodopa) and 7(carbidopa) below.

TABLE 6 Uniformity of Dispensed Content of Levodopa Samples on Stability5° C.: 8 5° C.: 8 5° C.: 15 5° C.: 15 weeks weeks weeks weeks Dispensed5° C.: 0 5° C.: 8 30° C.: 30° C.: 5° C.: 15 30° C.: 30° C.: Fractionweeks weeks 24 hrs 48 hrs weeks 24 hrs 48 hrs 1 102.1 103.0 103.5 103.3101.6 100.7 102.6 2 102.1 102.0 102.8 102.6 99.8 100.6 101.4 3 100.0103.4 103.3 103.1 98.7 100.6 102.2 4 101.9 103.4 103.3 103.7 99.0 101.6101.9 5 101.6 103.1 102.0 102.8 98.9 101.9 102.0 6 101.6 103.6 104.099.7 103.1 100.9 102.0 7 101.9 103.6 104.1 103.7 101.7 97.3 102.4 8101.2 104.0 104.5 103.7 101.9 102.7 102.6 9 100.1 104.1 104.0 104.3102.2 102.4 102.5 10  99.6 103.7 104.4 103.7 102.1 104.1 102.0

TABLE 7 Uniformity of Dispensed Content of Carbidopa Samples onStability 5° C.: 8 5° C.: 8 5° C.: 15 5° C.: 15 weeks weeks weeks weeksDispensed 5° C.: 0 5° C.: 8 30° C.: 30° C.: 5° C.: 15 30° C.: 30° C.:Fraction weeks weeks 24 hrs 48 hrs weeks 24 hrs 48 hrs 1 102.0 102.5102.4 101.4 100.4 98.5 99.7 2 102.0 100.9 101.3 101.3 98.6 98.8 99.1 399.5 102.0 101.5 101.2 96.9 98.1 99.5 4 101.0 101.7 101.5 101.7 97.099.4 99.2 5 100.5 101.6 100.1 100.5 96.8 99.4 99.4 6 100.8 102.0 101.697.7 99.5 98.3 99.3 7 100.9 102.0 101.8 101.8 98.1 94.7 99.3 8 100.3101.9 101.7 101.3 99.2 99.8 99.3 9 99.3 101.9 101.8 101.7 98.7 99.3 99.410  98.4 101.7 101.7 101.5 99.3 100.8 99.1

Example 3—Therapeutic Effect of Pharmaceutical Composition in Mini-Pigs

High concentration L-dopa/carbidopa intestinal gel was compared with alow concentration L-dopa/carbidopa intestinal gel and tested in thefollowing manner: A group of four minipigs each was administered LCL-dopa/carbidopa intestinal gel, HC L-Dopa/carbidopa intestinal gel, orL-dopa/carbidopa in a Carbopol carrier in a cross-over study design.Each of four mini-pigs was administrated with one formulation at thefirst day of a week, followed by 1-week washout period before the secondformulation was administered. The third formulation was administered tothe same mini-pigs after another week of washout period.

Total Dose: 11.07 mg/kg levodopa dose over 6.5 hrs.; 20 mg/mL

Groups: LC; HC; Carbopol

Bolus dose: 2.53 mg/kg over 30 min Bolus doseInfusion dose: 8.54 mg/kg over 6 hrs.

Bolus Infusion Rate:

-   -   LC=0.253 mL/kg/hr (For example: 10 kg pig=2.53 mL/hr pump rate)    -   HC=0.127 mL/kg/hr (For example: 10 kg pig=1.27 mL/hr pump rate)    -   Carbopol=0.127 mL/kg/hr (For example: 10 kg pig=1.27 mL/hr pump        rate)

6 hr Infusion Rate:

-   -   LC=0.071 mL/kg/hr (For example: 10 kg pig=0.71 mL/hr pump rate)    -   HC=0.0355 mL/kg/hr (For example: 10 kg pig=0.355 mL/hr pump        rate)    -   Carbopol=0.0355 mL/kg/hr (For example: 10 kg pig=0.355 mL/hr        pump rate).        Plasma sampling Time points: 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12        h

The results of the study confirm that the high concentrationlevodopa/carbidopa intestinal gel demonstrates comparable C_(max),T_(max) and AUC values to the LC formulation when administered underhalf hour bolus and 6 hour infusion conditions, as shown in FIGS. 2 and3. Cassettes of levodopa at 11.07 mg/kg and of carbidopa monohydrate at2.77 mg/kg were dosed at 80 μL/kg (LC gel) or 40 μL/kg (HC gel andCarbopol control). Bioavailability of levodopa is summarized in Table 8below. The half lives in Table 8 are calculated as harmonic means.

TABLE 8 Levodopa plasma concentration Mean Parameter Pig 1 Pig 2 Pig 3Pig 4 (SEM) C_(max) (μg/mL) 3.36 2.84 2.30 2.25 2.69 (0.26) LC gelT_(max) (h) 6.5 0.5 0.5 0.5 2.0 (1.5) AUC 23.7 19.1 10.4 10.2 15.9(3.35) (μg · h/mL) t_(1/2) (h) 1.0 0.9 0.9 2.2 1.1 C_(max) (μg/mL) 4.233.09 1.70 2.45 2.87 (0.53) HC gel T_(max) (h) 6.5 4.0 0.5 0.5 2.9 (1.5)AUC 27.6 21.8 9.88 12.3 17.9 (4.13) (μg · h/mL) t_(1/2) (h) 1.3 1.1 1.01.3 1.2 C_(max) (μg/mL) 3.03 3.39 1.95 2.62 2.75 (0.31) Carbopol T_(max)(h) 6.5 1.0 0.5 0.5 2.1 (1.5) AUC 20.6 22.1 9.56 13.4 16.4 (2.97) (μg ·h/mL) t_(1/2) (h) 1.2 1.0 0.9 1.0 1.0Bioavailability of carbidopa is summarized in Table 9 below.

TABLE 9 Carbidopa plasma concentration Mean Parameter Pig 1 Pig 2 Pig 3Pig 4 (SEM) C_(max) (ng/mL) 92 132 20 17 65 (28) LC gel T_(max) (h) 0.50.5 0.5 0.5 0.5 (0)   AUC (ng · h/mL) 374 348 18 23 191 (99)  C_(max)(ng/mL) 192 151 40 36 105 (39)  HC gel T_(max) (h) 0.5 0.5 0.5 0.5 0.5(0)   AUC (ng · h/mL) 751 393 41 47 308 (169) C_(max) (ng/mL) 204 369 2832 158 (81)  Carbopol T_(max) (h) 0.5 0.5 1.0 0.5 0.63 (0.13) AUC (ng ·h/mL) 578 660 36 38 328 (169)

Example 4: Further Bioavailability Studies in Human Subjects

To further test the bioavailability of the LC and HC formulationsdiscussed in Example 3 above, a total of 12 subjects participated in anopen label, single dose, randomized crossover study to test thebioavailability of the LC and HC formulations. Each subject received asingle dose of levodopa (200 mg) and carbidopa monohydrate (50 mg) onthe mornings of Day 1 and Day 4 under fasting conditions. Subjects wererandomly assigned in equal numbers to the two sequences of commerciallyprepared LC formulation of and commercially prepared HC formulation.Each dose was administered over a 30 minute period via nasojejunal tubeconnected to a portable infusion pump. Patients receiving the LCformulation received a 10.0 mL dose. Patients receiving the HCformulation received a 5.0 mL dose, so that equal amounts of drug weredelivered regardless of whether LC or HC formulation was administered.Subjects were confined for approximately 6 days (Check-in Day to Day 5).Serial blood samples for levodopa, carbidopa, and 3-O-methyldopa assayswere collected after dosing on Day 1 and Day 4. Times for collectioninclude 0 hour (prior to dose), at 5, 10, 15, 30, 45 minutes after thestart of infusion, and at 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours afterthe start of infusion. Bioavailability for levodopa is summarized inTable 10 below and in FIG. 4.

TABLE 10 Levodopa plasma concentration from test subjects (N = 12)Pharmacokinetic 200 mg Levodopa in LC 200 mg Levodopa in HC Parametersgel (% CV) gel (% CV) C_(max) (ng/mL) 2100 (35) 2100 (25) T_(max) (h) 0.85 (18)  0.81 (33) AUC_(t) (ng · h/mL) 4000 (18) 3930 (21) AUC_(∞)(ng · h/mL) 4080 (17) 4010 (20) t_(1/2) ^(a) (h)  1.69 (12)  1.85 (32)

Bioavailability for carbidopa is summarized in Table 11 below and inFIG. 5.

TABLE 11 Carbidopa plasma concentration from test subjects (N = 12)Pharmacokinetic 50 mg Carbidopa in LC 50 mg Carbidopa in HC Parametersgel (% CV) gel (% CV) C_(max) (ng/mL) 242 (79) 220 (45) T_(max) (h) 3.0(31) 2.5 (42) AUC_(t) (ng · h/mL) 956 (35) 910 (45) AUC_(∞) (ng · h/mL)1100 (30) 1070 (39) t_(1/2) ^(a) (h) 1.82 (14) 1.76 (18)

These tests show that the HC formulation was equal to the LC formulationfor levodopa C_(max), AUC_(t) and AUC_(∞) and for carbidopa AUC_(t) andAUC_(∞). The 90% confidence interval for equal carbidopa C_(m)ax isslightly beyond the 0.8 to 1.25 range. However, this is not a clinicallyrelevant factor because dosing for efficacy is determined by thelevodopa content, and not carbidopa. Studies show that peripheral dopadecarboxylase is saturated by carbidopa at approximately 70-100 mg aday, and advanced Parkinson's disease patients on levodopa/carbidopa geltreatment would surpass these daily carbidopa doses for saturation. Therelative bioavailability of the LC and HC formulations for levodopa andcarbidopa are summarized in Table 12 below.

TABLE 12 Bioequivalency of LC and HC gel formulations Relativebioavailability Central value Point 90% Parameter HC LC estimateConfidence C_(max) (ng/mL) 2040 1980 1.028 (0.859, 1.231) LevodopaAUC_(t) (ng · h/mL) 3860 3890 0.991 (0.922, 1.065) AUC_(∞) (ng · h/mL)3940 3970 0.993 (0.926, 1.065) C_(max) (ng/mL) 198 205 0.963 (0.739,1.253) carbidopa AUC_(t) (ng · h/mL) 835 903 0.925 (0.831, 1.029)AUC_(∞) (ng · h/mL) 887 965 0.919 (0.824, 1.025)

In summary, the amount of drug delivered was similar for bothformulations. Doses delivered for both formulations were similar (˜6%difference). Levodopa and carbidopa exposures were very similar for bothformulations. Levodopa exposure variability was low to moderate (17-35%CV) for both the LC and HC formulations. Both the LC and HC formulationswere equivalent for levodopa. The LC and HC formulations were equivalentfor carbidopa except for the C_(max) which is not clinicallysignificant.

FIGS. 6 & 7 show that the LC and HC formulations have similardissolution rates at pH 4.5 and 6.8, which supports the bioequivalencyresults summarized above. These dissolution trials were conducted byadding equal doses of drug formulations to beakers containing 500 mL of50 mM sodium acetate buffer at pH 4.5 (±0.05) or pH 6.8 (±0.05). Eachsample was maintained at 37° C. with agitation at 50 RPM during theprocedure. Samples were drawn at 5, 10, 15, 20, 30, 45, and 60 minutespost addition of drug. The concentration of drug dissolved in thesamples was measured by HPLC on a PHENOMENEX KINETEX C8 column (100×4.6mm, 5 μm with SecurityGuard Cartridge) at 30° C. The mobile phase was88:12 10 mM sodium heptane sulfonic acid (HAS) in 0.2% H₃PO₄:acetonitrile. The sample was eluted through the column at a rate of ˜3.0mL/min and measured by UV spectrophotometry (OD₂₈₀).

Example 5: Sedimentation and Storage Stability

Stokes' Law can be used to assess particle sedimentation and thus thephysical stability of the HC formulation. Stokes' Law considers threeforces acting on a particle situated in a continuous viscous fluid:buoyancy force, drag force, and gravitational force. When the forces arebalanced and there is no net acceleration, the particle reaches aterminal or settling velocity given by:

v=(d ²(ρ₁−ρ₂)g)/18η=(2r ²(ρ₁−ρ₂)g)/9η

where v is the settling velocity; d is the particle diameter and r isthe particle radius; ρ₁ is the density of the dispersed phase and ρ₂ isthe density of the dispersion medium; g is the gravity constant; η isthe viscosity of the fluid at rest.

There are two factors that can be controlled in the HC formulation tomodulate physical stability: particle size of levodopa and carbidopamonohydrate and viscosity of the gel-suspension. Levodopa and carbidopamonohydrate particle sizes are well controlled by the micronizationprocess within the particle size limits mentioned herein. However, theviscosity can be adjusted by modifying the ratio of carmellose sodiumviscosity grades. The viscosity of the fluid at rest is approximated bythe low shear viscosity method. The minimum low shear viscositynecessary to achieve the desired physical stability is 44,590 cps basedon this example, as shown in Tables 13 and 14.

TABLE 13 Acceptance Values for Levodopa Lot 1 Lot 2 Lot 3 Lot 4 Lot 5Lot 6 Interval LS Viscosity 32,393 36,692 39,692 44,590 45,590 45,790(cps) Release AV 4.9 5.0 6.1 4.1 3.7 3.9 15 weeks AV 26.1 31.2 20.6 4.72.8 3.1 at 5° C. Result Fail Fail Fail Pass Pass Pass

TABLE 14 Acceptance Values for Carbidopa Lot 1 Lot 2 Lot 3 Lot 4 Lot 5Lot 6 Interval LS Viscosity 32,393 36,692 39,692 44,590 45,590 45,790(cps) Release AV 3.6 4.7 3.8 5.2 5.3 4.4 15 weeks AV 10 8.4 6.4 0.7 1.81.9 at 5° C. Result Fail Fail Fail Pass Pass Pass

The criterion for “acceptable” physically stable was the absence ofsignificant sedimentation for at least 15 weeks under refrigeratedstorage conditions (e.g., 5° C.). The physical stability was assessed bydrawing 5 ml samples from the DDR for a total of 10 samples and thenanalyzing them for levodopa and carbidopa content using a high pressureliquid chromatography (HPLC) system with guard column: Agilent, ZorbaxEclipse XDB-C8, 4.6×12.5 mm, 5 μm (Agilent, part number 820950-926) withAgilent Hardware kit High Press, (Agilent, Part number 820999-901) orequivalent; and analytical column: Zorbax Eclipse XDB-C8, 150×4.6 mm, 5μm (Agilent part no. 993967-906). The chromatographic conditions areshown in Table 15.

TABLE 15 Chromatographic Conditions for Levodopa/Carbidopa ConcentrationTest Flow Rate ~1.2 mL/min. Injection Volume 5 μL Autosampler Temp. 5°C. Column Temp. ~30° C. Sample Diluent 0.1M phosphoric acid in waterMobile phase A 10 mM sodium heptane sulfonic acid in 0.2% phosphoricacid Mobile phase B Acetonitrile % Time (min.) % Mobile phase A Mobilephase B Isocratic Profile 0 88 12 Run Time Approximately 12 to 15minutes

A sample was defined as physically stable if the Acceptance Value (AV),defined by Equation 2, was no more than 15 for both levodopa andcarbidopa.

AV=|M−X|+ks  Equation 2.

The definition of each variable in Equation 2 is shown in Table 16.

TABLE 16 Definition of Variables Used in Calculating the AcceptanceValue Variable Definition Conditions Value X Mean of individual contents(X₁, X₂, . . . , X_(n)), expressed as a percentage of the label claimX₁, X₂, Individual contents of the . . . , X_(n) units tested, expressedas a percentage of the label claim n Sample size (# of units in sample)k Acceptability constant If n = 10, then k = 2.4 If n = 30, then k = 2.0s Sample standard deviation$\left\lbrack \frac{\sum\limits_{i = 1}^{n}\; \left( {\chi_{1} - \overset{\_}{X}} \right)^{2}}{n - 1} \right\rbrack^{\frac{1}{2}}$RSD Relative standard 100s/X deviation (the sample standard deviationexpressed as a percentage of the mean) M Reference value to be If 98.5%≤ X ≤ M = X (AV = ks) (case 1) applied where T ≤ 101.5 101.5% If X <98.5% M = 98.5% (AV = 98.5 − X + ks) If X > 101.5% M = 101.5% (AV = X −101.5 + ks) M Reference value to be If 98.5 ≤ X ≤ T M = X (AV = ks)(case 2) applied where T > 101.5 If X < 98.5% M = 98.5% (AV = 98.5 − X +ks) If X > T M = T % (AV = X − T + ks)

Example 6: Effect of Oxygen

The high concentration formulation can be purged of oxygen duringmanufacturing and stored in containers with low oxygen permeation. Thissignificantly decreases the rate of degradation compared to aformulation manufactured and stored in ambient oxygen conditions.Depending on the packaging, the disposable drug reservoirs can have verylow oxygen content at the time of filling. These DDRs consist of a hardshell outer, an inner package, and tubings/connectors. The inner bagserves to maintain the O₂ content of the final drug product gel. TheEVA/EVOH/EVA bag has a very low O₂ permeability (oxygen transmissionrate for the EVA/EVOH/EVA sheet film was approximately 0.95 cc/(100in²*day). FIG. 11 charts the accumulation of DHPA breakdown product whenLC and HC gel formulations are left for 15 weeks 0.3 mm thickEVA/EVOH/EVA bags at 2-8° C. Moreover, N₂ sparging can be used in themanufacture process to purge oxygen. The combination of N₂ sparging andlow O₂ permeability EVA/EVOH/EVA bag ensures a very low overall O₂content.

To test the effects of this low 02 packaging, samples of LC gelformulation were not sparged with N₂ and were packaged in polyvinylchloride (PVC) bags. Samples of HC gel formulation were sparged with N₂and packaged in EVA/EVOH/EVA bags. Both sets of bags were monitored forthe development of DHPA, DHPPA, and hydrazine degradation products overtime. The results of these tests are shown in FIGS. 8-10 below. DHPA andDHPPA were analyzed using HPLC system with analytical column: Waters,X-Bridge, C8, 3.5 μm particles, 4.6×150 mm column (catalogue 186003055)or equivalent with a stationary phase of octylsilane chemically bondedto totally porous silica particles (USP L7); and guard column:Phenomenex Security Guard Cartridge PFP 4×3.0 mm (catalogue AJ0-4290) orequivalent, security guard cartridge holder, Phenomenox, (catalogueAJO-6071) or equivalent. HPLC settings for the DHPA and DHPPA tests areshown in Table 17 below.

TABLE 17 Chromatographic Conditions for DHPA/DHPPA Test Wavelength 220nm Flow Rate 1.3 ± 0.2 mL/min Injection Volume 20 μL Autosampler Temp. 8± 2° C. Column Temp. 30 ± 1° C. Sample Diluent 0.1M Phosphoric acid inwater Mobile phase A 10% phosphate buffer, 10% 0.1M sodium heptanesulfonic acid and 80% water Mobile phase B 10% phosphate buffer, 10%0.1M sodium heptane sulfonic acid, 20% Acetonitrile and 60% water % Time(min.) % Mobile phase A Mobile phase B Gradient Profile 0 85 15 18.3 2575 19.0 25 75 20.0* 85 15 27.0* 85 15 *Gradient equilibration time

Hydrazine was analyzed using HPLC with a Grace Scientific column,Grom-Sil 120 ODS-5, 250×4.6 mm, 5 μm (Part No. GS0D50512S2505) orequivalent after the sample was eluted from SPE column: Chromabond® HR-X(15 mL/1000 mg) by Macherey-Nagel, Part No. 730941. HPLC settings forthe hydrazine tests are shown in Table 18 below.

TABLE 18 Chromatographic Conditions for Hydrazine Test Wavelength 313 nmFlow Rate 1.0 mL/min Injection Volume 30 μL Autosampler 5° C. Temp.Column Temp. 40° C. Sample Diluent 50 mM sulfuric acid in water; 1%solution of benzaldehyde in methanol; 100 mM solution of sodium boratein water Mobile phase A Purified water Mobile phase B AcetonitrileIsocratic Profile 30% A, 70% B Run Time 18 minutes

Degradation can also be slowed by adding oxygen scavengers (e.g. eitherferrous or non-ferrous based, canister or sachet) and placing into a lowO₂ permeability secondary container. The effects of oxygen scavengers indifferent packages on the accumulation of DHPA and DHPPA degradationproducts are illustrated in FIG. 11 below.

Although the invention has been described with respect to specificembodiments and examples, it should be appreciated that otherembodiments utilize the concept of the present invention are possiblewithout departing from the scope of the invention. The present inventionis defined by the claimed elements, and any and all modifications,variations, or equivalents that fall within the true spirit and scope ofthe underlying principles.

VIII. FURTHER EMBODIMENTS Embodiment 1

A pharmaceutical composition comprising a levodopa active agent and acarbidopa active agent for intraduodenal administration wherein thelevodopa active agent and the carbidopa active agent are suspended in anaqueous carrier, characterized in that the levodopa active agent and thecarbidopa active agent in the carrier has a high shear viscosity of nomore than about 4500 cps at room temperature and a low shear viscosityof no less than about 45000 cps under refrigerated conditions and aratio of low shear viscosity to high shear viscosity of not less than10.

Embodiment 2

The pharmaceutical composition according to Embodiment 1, wherein thepharmaceutical composition comprises: a levodopa active agent in anamount of about 4.0 weight/weight percent of the total composition; acarbidopa monohydrate active agent in an amount of about 1.0weight/weight percent of the total composition; a liquid vehicle (e.g.,in an amount of from about zero percent to about 95 weight/weightpercent of the total composition and/or selected from the groupconsisting of water), and wherein the aqueous carrier comprises asuspending agent (e.g., one or more polymer-based suspending agent, suchas an acrylic acid-based polymer or a polymer selected from the groupconsisting of hydroxypropylcellulose, hydroxymethylcellulose, and sodiumcarboxymethyl cellulose).

Embodiment 3

The pharmaceutical composition according to Embodiment 1 or 2, whereinthe pharmaceutical composition does not experience degradation into DHPAat a rate faster than 0.04 w/w % per week.

Embodiment 4

The pharmaceutical composition according to any one of the previousEmbodiments, wherein the pharmaceutical composition does not experiencedegradation into DHPPA at a rate faster than 0.04 w/w % per week.

Embodiment 5

The pharmaceutical composition according to any one of the previousEmbodiments, wherein the pharmaceutical composition does not experiencedegradation producing hydrazine at a rate faster than 0.6 μg/g per week.

Embodiment 6

The pharmaceutical composition according to any one of the previousEmbodiments, wherein the pharmaceutical composition is present in alower O₂ permeable primary or secondary container.

Embodiment 7

A pharmaceutical dosage form comprising the pharmaceutical compositionof any one of the previous Embodiments in a disposable drug reservoirhaving an oxygen impermeable enclosure disposed therein, wherein theoxygen impermeable enclosure is purged with an inert gas and an oxygenscavenger is added, and optionally, wherein the pharmaceutical dosageform is suitable for use in a continuous infusion pump capable ofdelivering the composition in a therapeutically effective manner.

Embodiment 8

A method of preparing the pharmaceutical composition according to anyone of Embodiments 1-6, wherein the method comprises: adding a levodopaactive agent and a carbidopa active agent to water to form a slurry;adding the slurry to one or more suspending agents (e.g., an acrylicacid-based polymer or a polymer selected from the group consisting ofhydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethylcellulose) to form a suspension; subjecting the suspension to N₂sparging; and optionally, loading the suspension into a lower oxygenpermeability container.

Embodiment 9

The method according to Embodiment 8, wherein, prior to forming thesuspension, the levodopa active agent has a particle size distributionof: (i) D50 less than or equal to about 5 μm; (ii) D90 less than orequal to about 11 μm; and (iii) D100 less than or equal to about 22 μm;and the carbidopa active agent has a particle size distribution of: (i)D50 less than or equal to about 3 μm; (ii) D90 less than or equal toabout 7 μm; and (iii) D100 less than or equal to about 21 μm.

Embodiment 10

The pharmaceutical composition according to any one of Embodiments 1-6prepared by: adding a levodopa active agent and a carbidopa active agentto water to form a slurry; adding the slurry to one or more suspendingagents (e.g., an acrylic acid-based polymer or a polymer selected fromthe group consisting of hydroxypropylcellulose, hydroxymethylcellulose,and sodium carboxymethyl cellulose) to form a suspension; subjecting thesuspension to N₂ sparging; and optionally, loading the suspension into alower oxygen permeability container.

Embodiment 11

The pharmaceutical composition according to Embodiment 10, wherein,prior to forming the suspension, the levodopa active agent has aparticle size distribution of: (i) D50 less than or equal to about 5 μm;(ii) D90 less than or equal to about 11 μm; and (iii) D100 less than orequal to about 22 μm; and the carbidopa active agent has a particle sizedistribution of: (i) D50 less than or equal to about 3 μm; (ii) D90 lessthan or equal to about 7 μm; and (iii) D100 less than or equal to about21 μm.

Embodiment 12

A method of treating Parkinson's disease in a patient in need thereof,wherein the method comprises administering to the patient apharmaceutical composition comprising a levodopa active agent and acarbidopa active agent for intraduodenal administration, wherein thelevodopa active agent and carbidopa active agent are provided in atherapeutically effective manner for the patient and, suspended in anaqueous carrier, characterized in that the levodopa active agent and thecarbidopa active agent in the carrier has a high shear viscosity of nomore than about 4500 cps at room temperature and a low shear viscosityof no less than about 45000 cps under refrigerated conditions and aratio of low shear viscosity to high shear viscosity of not less than 10and optionally, wherein the pharmaceutical composition is administeredin a pharmaceutical dosage form according to Embodiment 7.

Embodiment 13

The method according to Embodiment 12, wherein the method comprisessubstantially continuous administration of the pharmaceuticalcomposition for a period of at least about 16 hours or for a period ofat least about 24 hours.

Embodiment 14

The method according to Embodiment 12 or 13, wherein the pharmaceuticalcomposition comprises: a levodopa active agent in an amount of about 4.0weight/weight percent of the total composition; and a carbidopamonohydrate active agent in an amount of about 1.0 weight/weight percentof the total composition.

Embodiment 15

The method according to any one of Embodiments 12-14, wherein theaqueous carrier comprises one or more polymer-based suspending agent(e.g., an acrylic acid-based polymer or a polymer selected from thegroup consisting of hydroxypropylcellulose, hydroxymethylcellulose, andsodium carboxymethyl cellulose).

Embodiment 16

A kit comprising the pharmaceutical composition of any one ofEmbodiments 1-6 or the pharmaceutical dosage form of Embodiment 7.

1. A pharmaceutical composition for intraduodenal administrationcomprising: (a) a levodopa active agent in an amount of about 4.0weight/weight percent of the total composition; (b) a carbidopamonohydrate active agent in an amount of about 1.0 weight/weight percentof the total composition; (c) one or more acrylic acid-based polymersuspending agents; and (d) water, wherein the pharmaceutical compositionhas: (i) a high shear viscosity of no more than about 4500 cps at 22° C.and 24.1 s⁻¹; (ii) a low shear viscosity of no less than about 45000 cpsat 5° C. and 1 s⁻¹; and (iii) a ratio of low shear viscosity to highshear viscosity of not less than
 10. 2-5. (canceled)
 6. Thepharmaceutical composition according to claim 1, wherein the one or moreacrylic acid-based polymer suspending agents is Carbopol®.
 7. Thepharmaceutical composition according to claim 1, wherein theconcentration of water is in an amount of from about zero percent toabout 95 weight/weight percent of the total composition.
 8. (canceled)9. (canceled)
 10. The pharmaceutical composition according to claim 1,wherein the pharmaceutical composition does not experience degradationinto DHPA at a rate faster than 0.06 w/w % per week.
 11. Thepharmaceutical composition according to claim 1, wherein thepharmaceutical composition does not experience degradation into DHPPA ata rate faster than 0.06 w/w % per week.
 12. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical compositiondoes not experience degradation producing hydrazine at a rate fasterthan 0.75 μg/g per week.
 13. The pharmaceutical composition according toclaim 1, wherein the pharmaceutical composition is present in a lower O₂permeable primary or secondary container.
 14. A pharmaceutical dosageform comprising the pharmaceutical composition of claim 1 in adisposable drug reservoir having an oxygen impermeable enclosuredisposed therein, wherein the oxygen impermeable enclosure is purgedwith an inert gas and an oxygen scavenger is added.
 15. Thepharmaceutical dosage form according to claim 14, wherein thepharmaceutical dosage form is suitable for use in a continuous infusionpump capable of delivering the composition in a therapeuticallyeffective manner.
 16. A method of preparing a pharmaceutical compositionfor intraduodenal administration comprising: (a) a levodopa active agentin an amount of about 4.0 weight/weight percent of the totalcomposition; (b) a carbidopa monohydrate active agent in an amount ofabout 1.0 weight/weight percent of the total composition; (c) one ormore polymer-based suspending agents; and (d) water, wherein thepharmaceutical composition has: (i) a high shear viscosity of no morethan about 4500 cps at 22° C. and 24.1 s⁻¹; (ii) a low shear viscosityof no less than about 45000 cps at 5° C. and 1 s⁻¹; and (iii) a ratio oflow shear viscosity to high shear viscosity of not less than 10, whereinthe method comprises: adding a levodopa active agent and a carbidopamonohydrate active agent to water to form a slurry; adding the slurry toone or more polymer-based suspending agents to form a suspension; andsubjecting the suspension to N₂ sparging.
 17. The method according toclaim 16, further comprising loading the suspension into a lower oxygenpermeability container.
 18. The method according to claim 16, wherein,prior to forming the suspension, the levodopa active agent has aparticle size distribution of: (i) D50 less than or equal to about 5 μm;(ii) D90 less than or equal to about 11 μm; and (iii) D100 less than orequal to about 22 μm; and the carbidopa active agent has a particle sizedistribution of: (i) D50 less than or equal to about 3 μm; (ii) D90 lessthan or equal to about 7 μm; and (iii) D100 less than or equal to about21 μm.
 19. The method according to claim 16, wherein the one or morepolymer-based suspending agents is selected from the group consisting ofhydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethylcellulose.
 20. The method according to claim 16, wherein the one or morepolymer-based suspending agent is an acrylic acid-based polymer. 21-25.(canceled)
 26. A method of treating Parkinson's disease in a patient inneed thereof, wherein the method comprises intraduodenal administrationto the patient a pharmaceutical composition comprising: (a) a levodopaactive agent in an amount of about 4.0 weight/weight percent of thetotal composition; and (b) a carbidopa monohydrate active agent in anamount of about 1.0 weight/weight percent of the total composition; (c)one or more polymer-based suspending agents; and (d) water, wherein thepharmaceutical composition has: (i) a high shear viscosity of no morethan about 4500 cps at 22° C. and 24.1 s⁻¹; (ii) a low shear viscosityof no less than about 45000 cps at 5° C. and 1 s⁻¹; and (iii) a ratio oflow shear viscosity to high shear viscosity of not less than
 10. 27. Themethod according to claim 26, wherein the method comprises substantiallycontinuous administration of the pharmaceutical composition for a periodof at least about 16 hours. 28-31. (canceled)
 32. The method accordingto claim 26, wherein the one or more polymer-based suspending agent isselected from the group consisting of hydroxypropylcellulose,hydroxymethylcellulose, and sodium carboxymethyl cellulose. 33.(canceled)
 34. The method according to claim 26, wherein the one or morepolymer-based suspending agent is an acrylic acid-based polymer
 35. Akit comprising the pharmaceutical composition of claim
 1. 36. A kitcomprising the pharmaceutical dosage form of claim 14.